title: Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity.
abstract: Homologous recombination mediates error-free repair of DNA double-strand breaks (DSB). RAD51 is an essential protein for catalyzing homologous recombination and its recruitment to DSBs is mediated by many factors including RAD51, its paralogs, and breast/ovarian cancer susceptibility gene products BRCA1/2. Deregulation of these factors leads to impaired DNA repair, genomic instability, and cellular sensitivity to chemotherapeutics such as cisplatin and PARP inhibitors. microRNAs (miRNA) are short, noncoding RNAs that posttranscriptionally regulate gene expression; however, the contribution of miRNAs in the regulation of homologous recombination is not well understood. To address this, a library of human miRNA mimics was systematically screened to pinpoint several miRNAs that significantly reduce RAD51 foci formation in response to ionizing radiation in human osteosarcoma cells. Subsequent study focused on two of the strongest candidates, miR-103 and miR-107, as they are frequently deregulated in cancer. Consistent with the inhibition of RAD51 foci formation, miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA-damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. Furthermore, endogenous regulation of RAD51D by miR-103/107 was observed in several tumor subtypes. Taken together, these data show that miR-103 and miR-107 overexpression promotes genomic instability and may be used therapeutically to chemosensitize tumors.
  
  
  CONCLUSIONS
  These findings demonstrate a role for miR-103 and -107 in regulating DNA damage repair, thereby identifying new players in the progression of cancer and response to chemotherapy.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-015, Seattle, WA 98109-1024. ttaniguc@fhcrc.org.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Huang
authors.forename: Yemin
authors.initials: Y
authors.lastname: Wang
authors.forename: Kiranjit K
authors.initials: KK
authors.lastname: Dhillon
authors.forename: Philamer
authors.initials: P
authors.lastname: Calses
authors.forename: Emily
authors.initials: E
authors.lastname: Villegas
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Mitchell
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000378:metabolism*; D059767:Recombinational DNA Repair / Q000187:drug effects / Q000528:radiation effects
chemical_list: D004268:DNA-Binding Proteins; C544749:MIRN103 microRNA, human; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D010793:Phthalazines; D010879:Piperazines; C112629:RAD51D protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin; C531550:olaparib